Adalimumab in the management of psoriasis and psoriatic arthritis: Results from a Delphi investigation

Abstract Background and Objectives Psoriasis (PsO) and psoriatic arthritis (PsA) are often undertreated and require a multidisciplinary approach. In recent years, patent expiration has allowed the introduction of tumor necrosis factor inhibitor (anti-TNF) biosimilars, which have stimulated a significant increase in the use of biological therapies. This article reports the findings of a multidisciplinary approach to achieve a consensus on the use of adalimumab in patients with PsO or PsA. Methods A voting panel of 36 Italian dermatologists and rheumatologists were chosen by eight Italian clinicians (the Board), to provide a consensus on the real-world management of PsO and PsA with adalimumab using the Delphi Method, comprising three survey rounds. Twelve statements were defined by the Board and submitted to the panel (rating scale 1–7). Results Clinicians reached a wide consensus on the effectiveness (score 6–7: 67%) and long-term efficacy (6–7: 100%) of adalimumab in all clinical forms of PsO and PsA, including pediatric patients (6–7: 85%). Considering cost-effectiveness and safety, adalimumab is suggested as a first-line treatment in patients with enthesitis, predominant peripheral arthritis, axial involvement or associated inflammatory bowel disease (IBD) or uveitis. Adalimumab can be also considered after failure of etanercept (6–7: 94%). Conclusion Results from this Delphi study clearly show an overall consensus on the use of adalimumab in the management of PsO and PsA, particularly as first-choice for specific subpopulations (uveitis, IBD, hidradenitis suppurativa). Considering the cost-effectiveness of biosimilars within Italy, adalimumab may represent an effective and safe first-line treatment for patients with moderate-to-severe PsO or PsA, and a valid choice for switching after failure.


Introduction
Immune-mediated inflammatory diseases (IMIDs) are chronic disorders sharing common epidemiological and genetic features, and underlying pathogenetic pathways. [1,2]Indeed, evidence suggests that multiple IMIDs may coexist in the same patient. [3]In the first year of disease, peripheral arthritis may occur in about 12% of patients with inflammatory bowel disease (IBD). [4]These patients are also prone to develop psoriasis (PsO) or rheumatoid arthritis (RA). [5]In women with PsO and psoriatic arthritis (PsA), the former is associated with a significantly increased risk of Crohn's disease. [6]A occurs in 0.04%-1% of the general population and between 20%-40% of PsO patients. [7,8]Metabolic, cardiovascular, [9] and psychological comorbidities overlap in PsO, with a significant impact on quality of life [10] and increased mortality. [11]The heterogeneous clinical presentation of PsA and PsO represents a clinical challenge when choosing a suitable therapy, in particular when treating concurrent comorbidities. [12]Undertreatment is also significant, [13,14] where up to 24% of patients with moderate-to-severe PsO are not treated, and 30% are only receiving topical therapy, which may not control the disease. [13]Similarly, PsA is a heterogeneous and potentially severe disease, which may require a multidisciplinary approach to treatment. [15] the last two decades, the number of disease-modifying antirheumatic drugs (DMARDs) has significantly increased. [16]The introduction of biologic DMARDs, such as tumor necrosis factor (TNF) inhibitors has greatly improved patients' quality of life, [1] with anti-TNFs often prescribed as first-line treatment for PsO and/or PsA. [15,17]uidelines also recommend anti-TNFs when there is an insufficient response to nonsteroidal anti-inflammatory drugs (NSAIDs) or local glucocorticoid injections. [1,15,18]In PsA, a biologic DMARD is recommended after an inadequate response to at least one conventional synthetic DMARD, while an interleukin (IL)-17 or IL-12/23 inhibitor may be preferred when there is significant skin involvement. [15]However, IL-17 inhibitor treatment has been associated with exacerbations of and new onset IBD or colitis.Fortunately, the cessation of IL-17 inhibitors and initiation of an alternative treatment (e.g., corticosteroids and anti-TNF therapy) can generally lead to clinical remission. [19,20]e efficacy and tolerability of adalimumab have been demonstrated in PsA, plaque PsO, RA and IBD (including Crohn's disease, ulcerative colitis, pediatric Crohn's disease, and pediatric ulcerative colitis), [21,22] Assessment of the clinical efficacy and cost-effectiveness of adalimumab has shown it to be a valid treatment choice in a large number of patients. [1]Two Italian studies have demonstrated that, economically, adalimumab is below the threshold value for health care interventions for all its main indications, as it significantly reduces societal costs for RA, PsO and PsA, ankylosing spondylitis, and Crohn's disease. [23,24]The longterm safety profile of adalimumab has also been well established in multiple clinical trials, [25] with infections being the most commonly reported serious adverse event, and in the real-world setting. [26,27] is generally accepted that patients with IMIDs should receive effective treatment as early as possible to prevent and limit organ damage, comorbidities, and the natural progression of the disease. [28]Recent patent expiration has introduced numerous anti-TNF biosimilars, which have markedly increased the overall uptake of biological therapies for patients with PsO. [29]Anti-TNF biosimilars provide cost reduction and increased patients' access to biological treatment, positively influencing the course of their disease. [1]e aim of the present work was to convene rheumatologists and dermatologists experienced in the use of anti-TNF agents, to achieve a consensus on the use of adalimumab in patients with PsO and/or PsA.

Materials and Methods
[30][31] The Delphi method is a highly regarded approach which involves an iterative process, characterised by multiple rounds of voting, to ascertain consensus on clinical matters in healthcare where there is limited guidance and/or a scarcity of evidence. [30] the present study, the methodology was stratified into four phases: [ 1] the Board identified 12 statements lacking clinical consensus and developed a Delphi questionnaire (Table 1), [ 2]  the questionnaire was then submitted to a panel of 36 Italian clinical experts in the field of PsO and PsA through an online platform for a first Delphi round.The voting panel were chosen by the Board members, who nominated 4-5 collaborators or colleagues, each operating in distinct geographic regions (e.g., North-East, North-West).Geographical criteria were adhered to, ensuring homogeneous coverage of the Italian national territory.The panel were then asked to express their agreement or disagreement on each item using a Likert-type scale from 1 to 7 (1 = strongly disagree to 7 = strongly agree) for a maximum of three rounds.[ 3] Responses were collected and analysed.[ 4] Common and conflicting viewpoints were identified.At the end of Round 1, the median value, the 25th (Q1) and 75th (Q3) percentiles and the interquartile range (IQR) of each statement were calculated.
In Round 2, experts were asked to answer the same statements taking into account the IQR of each question, as an index of the responses of their colleagues.In case of a score outside the IQR, experts were required to provide a reason.The results of the first and second rounds and the reasons were discussed by the Board, focusing on the motivations/theses of those who responded outside the IQR.After discussing and commenting on the results of each of the 12 statements, the Board members re-formulated the statements.
In Round 3, the panel were invited to express their agreement/disagreement with the same statements considering the antitheses and the new IQRs.At this time, those who answered outside the IQR were asked to provide a new motivation.The statements were ranked based on the Q1 and the IQR (Figure 1).The "level of agreement or disagreement" achieved was measured according to the following criteria: a) agreement and consent (Q1≥4, Q3 > 4 and IQR≤2), b) agreement and low consent (Q1≥4 and IQR≥ 3), c) indecision (Q1= Q3= 4 or Q1= 3 and Q3= 5), d) disagree and consent (Q1 < 4 and IQR ≤2 and Q1≠3 and Q1≠5) and e) disagree and low consent (Q1 < 4 and IQR≥3).

Statistical Analysis
Descriptive statistics (median and IQR) were used for the analysis of surveys in rounds.For each question and round the panel's changes of opinion and related IQRs are reported, where the IQR is defined as the absolute value of the difference between Q3 and Q1, with smaller values indicating higher degrees of consensus.Statistical analyses were performed using Stata Version 16.1.

Results
All 36 participants responded to Round 1, and 33 responded to the remaining two rounds.All statements reached a positive consensus, with variations in 29% of responses between the first and the second round, and in 17% of responses between the second and the third round.For the 4 statements with values outside the IQR (S6, S7, S9, and S12), the Board was asked to reclarify their statement to avoid confusion in  the observations provided by the expert panel (Table 2).

Consensus Statements
The final consensus for each item is summarized in Table 3.

Statement S1. A synergistic collaboration between dermatologists and rheumatologists may be very important
for a more comprehensive and personalized management of PsA and PsO patients.This statement showed a high level of agreement in Round 1, with a median equal to 7. In Round 3, 97% of the experts gave 7, the maximum agreement score, with the remaining 3% (1 expert) assigning a score of 6.A 15% variation in answers was observed between the first and the second round, while only 1 expert (3%) changed his answer between the other rounds.

Statement S2. Adalimumab is highly effective in all clinical forms of PsO (scalp, nails, palmoplantar, inverse, face).
A median response equal to 5 was obtained in Round 1.In Round 2, all responses were between 5 and 6, while in Round 3, 33% of the experts gave a score equal to 5, 64% assigned a score of 6, and only one expert (3%) assigned the highest score.A 45% variation in answers was observed between the first and the second round, while 7 experts (21%) changed their answers between the other rounds.The statement of the board specifically refers to ADA biosimilars, while the objection pertains to biosimilars in general when compared with first-line agents S7 2 I would consider, at least at the same level, an anti-IL-17 therapy in patients with enthesitis (scored 4)

Statement
We agree that both treatments are good candidates for the treatment of enthesitis.The question however was specifically related to ADA S9 2 Only the MAXIMISE study with secukinumab has demonstrated clinical efficacy of a biologic drug in axial PsA (scored 3) We agree that MAXIMISE is the only RCT on biotechnological drugs on axial PsA.However, TNF-blocking agents are currently recommended by GRAPPA and EULAR guidelines for the treatments of axial PsA.quality of life and ability to work with moderate-to-severe PsO and PsA [33] may profit from a reduction in disease burden and the indirect costs of PsO. [15,34]Moreover, adherence and patient satisfaction are higher with biologic agents when compared to conventional agents. [35,36] the present study, five statements in the Delphi questionnaire were based on the pathogenesis of IMIDs and the dysregulation of inflammatory cytokines.The inhibition of TNF results in a down-regulation of the abnormal inflammatory pathways implicated in the pathogenesis and progression of IMIDs, and anti-TNF inhibitors including adalimumab may improve long-term patient outcomes by preventing the development of future damage and comorbidities. [28]ong Delphi expert panel responses, adalimumab emerged as a drug with long-term sustained effectiveness in PsA and PsO.Moreover, the cost-effectiveness of adalimumab is a significant factor when considering treatment options for PsO and PsA.Therefore, the cumulative results of this study suggest that adalimumab offers a suitable first-line treatment for patients with PsO/PsA, offering an effective therapeutic option with an established long-term, risk/benefit profile.The panel also strongly agreed that adalimumab may be first choice for specific PsO and PsA subpopulations such as those with comorbid uveitis, IBD or hidradenitis suppurativa.The use of adalimumab in PsA patients with predominant enthesitis, and/ or peripheral arthritis, and/or axial involvement achieved a high agreement among the Board and expert panel.
In conclusion, the results of this Delphi exercise indicate the need to bridge the gap between patients' expectations and physicians' objectives, with a focus on improving the quality of life and personalized treatment of patients with PsO and PsA.Given the cost-effectiveness of biosimilars in Italy, adalimumab may represent an effective and safe first-line treatment for patients with moderate-to-severe PsO or PsA, as well as patients suffering from non-musculoskeletal symptoms affecting the gut (IBD) or the eyes (uveitis).

Figure 1 .
Figure 1.Flow diagram of the statement classification in terms of level of agreement or disagreement.IQR, interquartile range; Q, quartile.

Table 1 :
Delphi consensus statements considerations are very relevant in the choice of the treatment for patients with PsO and PsA S6 Based on effectiveness, safety and costs, a patient with PsO eligible for a systemic treatment is a good candidate for adalimumab biosimilar as firstline treament S7 Patients with PsA and predominant enthesitis are good candidates for treatment with adalimumab S8 Patients with PsA and predominant peripheral arthritis are good candidates for treatment with adalimumab S9 Patients with PsA and predominant axial involvement are good candidates for treatment with adalimumab S10Adalimumab is a drug of choice when PsO and/or PsA are associated with uveitis or hidradenitis suppurativa S11 Adalimumab is a drug of choice when PsA and/or PsO are associated with inflammatory bowel diseaseS12In patients with PsA and moderate skin involvement the switch to adalimumab can be considered after failure of etanercept PsA, psoriatic arthritis; PsO, psoriasis; S, statement.

S3. Pediatric patients (>= 4 years old) with mod- erate-to-severe PsO and eligible for a systemic therapy are good candidates for treatment with adalimumab
. The statement showed a high agreement from Round 1 (Table3).In Round 3, 33% of experts assigned the maximum agreement score of 7. A variation in responses of 24% was observed between Round 1 and Round 2, and 27% between Round 2 and Round 3.Statement S4.Adalimumab has a long-term sustained effectiveness in patients with PsA and PsO.A median score of 6 was achieved in Round 1.In Round 2, all responses were between 6 and 7.In Round 3, 30% of experts gave the maximum agreement score of 7, with the remaining 70% assigning a score of 6.A variation in responses of 24% was noted between Round 1 and Round 2, while three experts (9%) changed their answers in the other rounds.Statement S5.

Based on effectiveness, safety and costs, a patient with PsO eligible for a systemic treatment is a good candidate for adalimumab biosimilar as first-line treatment
Statement S7.Patients with PsA and predominant enthesitis are good candidates for treatment with adalimumab.A high agreement with a median of 6 was achieved in Round 1 and confirmed in Round 2. All the answers ranged between 6 and 7 in Round 3, where 39% of the experts gave the maximum agreement score of 7, and 61% gave a score

Table . 2
Thesis and antithesis motivation (in bracket the assigned score)

Statement S9. Patients with PsA and predominant axi- al involvement are good candidates for treatment with adalimumab
Statement S11.Adalimumab is a drug of choice whenPsA and/or PsO are associated with IBD.The highest median score of 7 was obtained in all rounds.A variation of 24% was seen in responses between Round 1 and 2.Statement S12.

In patients with PsA and moderate skin involvement, the switch to adalimumab can be consid- ered after failure of etanercept.
This statement received a high consensus among experts with a median score of 6 in Round 1.In Round 2, scores ranged between 6 and 7.In Round 3, 33% of the experts gave the maximum score of 7, and 61% gave a median score of 6.A variation of 36% in responses was detected between Round 1 and Round 2, while in Round 3, the answer was modified by 36% of the experts.